Bis-(1-piperidino) alkanes



United States 3,055,902 Patented Sept. 25, 1962 ICQ 3,055,902BIS-(l-PIPERIDINO) ALKANES Gordon Northrop Walker, Gillette, N.J.,assignor to Ciba Corporation, a corporation of Delaware No Drawing.Filed Aug. 4, 1959, Ser. No. 831,459 10 Ciaims. (Cl. 260-293) Thepresent invention concerns bis-piperidino-alkane compounds. Moreparticularly, it relates to compounds of the formula in which Alkrepresents an alkylene radical separating group Pi from group Pi by fourto twenty carbon atoms, and ,each of the groups Pi and Pi stands for anamino-1- piperidino group, N-acyl-ated derivatives, salts and quaternaryammt inium compounds thereof.

The alkylene radical Alk, which separates the amino-lpiperidino radicalsby from four to twenty carbon atoms, contains from four to twenty, moreespecially from six to fourteen, particularly from eight to twelve,primarily ten, carbon atoms, which may be arranged in a straight or in abranched chain. Such alkylene chains are, for example, 1,4-butylene,1,5'-pentylene, 1,6-hexylene, 1,7-heptylene, 1,8-octylene, 1,9-nonylene,1,10-decylene, 1,11-undecylene, 1,12-dodecylene, 1,13-tridecylene,1,l4-tetradecylene 1,15-pentadecylene, 1,16-hexadecylene,l,17-heptadecylene, 1,18-octadecylene, 1,19-nonadecylene, 1,20-eicosylene, I-methyLLS-pentylene, 3,3-di-methyl-l,5- pentylene,3,4-dimethyl-1,6-hexylene,4,4-dimethyl 1,7 hept ylene,2,7-dimethyl-1,8-octylene, S-ethyl 1,9 nonylene, l-methyl-1,l-decylene,5,6-diethyl-l,lO-decylene, 3,8-dimethyl-1,10-decylene and the like.

In the amino-lpiperidino moieties the amino group is located primarilyin the 4 position of the piperidyl nucleus, but may also be attached tothe 3position of the ring.

The amino group of the amino-l-piperidino portion represents above all aprimary amino group.

Amino may also stand for secondary amino, particularly N-loweralkyl-amino, e.g. N-methylamino, N-ethylamino, N-nqpropylamino,N-isopropylarnino and the like, N-carbocyclic arylamino, such asN-monocyclic carbocyclic aryl-amino, e.g. N-phenylamino and the like, orN-bicyclic carbocyclic aryl-amino, e.g. N-1-naphthyl-' amino orN-Z-naphthyl-amino and the like, or N-carbocyclic aryl-loweralkyl-amino, such as Nmonocyclic carbocyclic aryl-lower aIkyLamino, e.g. N-benzylamino, N-lphenylethylarnino or N-Z-phenylethyl-amino and thelike, or bicyclic carbocyclic aryl-lower alkyl-amino, e.g.N-lnaphthyl-methylamino and the like.

=1Also included as amino groups are tertiary amino groups, such as, forexample, N,N-di-lower alkyl-amino, e.g. N,N-dimethylamino,N-ethyl-Namethyl-amino, N,N- diethylamino, N,N-dipropylamino orN,N-di-isopropylamino and the like, N-lower alkyl-N-carbocyclicaryllower alkyl-amino, e.g. N-benzyl-N-methyl-amino or N-methyl-N-(2-phenylethyl)-amino and the like, or N-lower 'alkyl-N-lowercycloalkyl-amino, e.g. N-cyclopentyl-N- methyl-amino orN-cyclohexyl-N-methyl-amino and the like. Other tertiary amino groupsare, for example, N,N- alkylene-imino groups, in which alkylene containspreferably from four to eight carbon atoms, e.g. l-pyrrolidino,Zmethyl-l-pyrrolidino, l-piperidino, 2-methyl-1-piperidino,S-methyl-lpiperidino, 4amethyl-1-piperidino, 3-hydroxy-lpiperidino,3-acetoxy-1 piperidino, 3 hydroxymethyl-l-piperidino, N,N-lhexamethyleneimino, N,N,-lheptamethyleneimino and the like, N,N-loweroxa-alkyleneirnino, in which alkylene contains preferably four carbonatoms, e.g. morpholino, or N,N-lower aza-alkyleneimino, in whichalkylene contains preferably four carbon atoms, e.g. piper'azino,4-methyl-piperazino, 4-benzyl- 2 piperazino,4-(2-hydroxyethyl)-piperazino, 4-(2-acetoxyethyl)apiperazino and thelike.

N-acyl-amino may also represent the amino group of the amino-l-pipeiidylportion of the bis-(amino-l-piperidino)-alkanes of this invention. 'Acylrepresents primarily the acyl radical of organic carboxylic acids. Suchacids are, for example, aliphatic carboxylic acids, such as carbonicacids, especially O-lower alkyl-carbonic acids, e.g. oamethyl-carbonicor O-ethyl-carbonic acid and the like, O-carbocyclic aryl-loweralkyl-carbonic acids, e.g. O-benzyl-carbonic acid and the like, loweralkane carboxylic acids, which may contain other functional groups, e.g.formic, acetic, propionic, butyric, pivalic or trifluoroacetic acid andthe like, carbocyclic aryl carboxylic acids, which may containadditional substituents, such as monocyclic carbocyclic aryl carboxylicacids, e.g. benzoic acid and the like, or carbocyclic aryl-lower alkanecarboxylic acids, which may contain other groups, such as monocycliccarbocyclic aryl-lower alkanoic acids, e.g. phenylacetic, or3+phenyl-propionic acid and the like, or other organic carboxylic acids.

The piperidino nucleus of the amino-l-piperidino group is preferablyunsubstituted, or may contain one or more than one additionalisubstituent, which may be attached to any of the positions availablefor substitution in the aminol-piperidino nucleus. Such substituents areparticularly lower alkyl, e. g. methyl or ethyl and the like, halogen,e.g. fluorine, chlorine or bromine and the like, lower alkoxy, e.g.methoxy or ethoxy and the like, or other substituents.

Although the two amino-l-piperidino groups Pi and Pi, connected throughthe alkylene radical, may be of different nature, they are preferablyidentical.

Salts of the compounds of this invention are particularlytherapeutically acceptable acid addition salts with inorganic acids,such as mineral acids, e.g. hydrochloric, hydrobromic, sulfuric orphosphoric acids and the like, with organic carboxylic acids, e.g.formic, acetic, pro- ,pionic, glycolic, lactic, pyruvic, malonic,suocinic, maleic, hydroxymaleic, dihydydromaleic, fumaric, malic,tartaric, citric, benzoic, cinnamic, mandelic, salicyclic,4-a-minosalicylic, Z-phenoxybenzoic or 2-acetoxybenzoic, and the like,or with organic sulfonic acids, e.g. methane sulfonic, ethane sulfonicor 2-hydroxyethane sulfonic acids. Salts, which are primarily used foridentification purposes, are particularly those with acidic organicnitro compounds, e.g. picric, picrolonic or flavianic acid, or withmetal complex acids, e.g. phosphotungstic, phosphomolybdic,chloroplatinic or Reinecke acid. Mono-, more particularly poly-, such asbisor tetra-salts may be formed, depending on the procedure used for thepreparation of the salts and/ or the number of salt-forming groupspresent.

Quaternary ammonium derivatives of the compounds of this invention areparticularly those with reactive esters formed by hydroxylated compoundsand strong acids, particularly mineral acids, e.g. hydrochloric,hydrobromic or hydriodic acid and the like, or strong organic sulfonicacids, e.g. methane sulfonic, ethane sulfonic or Z-hydroxyethanesulfonic acid and the like. Such esters are, for example, lower alkylhalides, e.g. methyl, ethyl, n propyl or isopropyl chloride, bromide oriodide and the like, lower alkyl lower alkane sulfonates, e.g. methyl orethyl methane or ethane sulfonate and the like, or lower alkyl lowerhydroxy-alkane sulfonate, e.g. methyl Z-hydroxyethane sulfonate. Alsoincluded as quaternary ammonium compounds are the quaternary ammoniumhydroxides, and the salts obtained by reacting the latter withinorganic, or more particularly with organic acids, such as with thosedescribed hereinbefore as being suitable for the preparation of acidaddition salts. Monoor poly-quaternary ammonium compounds may be formed,depending to exterminate bacteria in an alkane dicarboxylic acids,

on the procedure used for their formation and/or the number of tertiaryamino groups present in the molecule.

The compounds may be in the form of mixtures of racemate's, which may beseparated into single racemates, or in the form of racemates, which maybe resolved into the antipodes.

The compounds of the present invention have COIlSlderable bacteriostaticand bactericidal effects and may, therefore, be used to prevent thepropagation and possibly animal or human host, without noticeableadverse effects to the latter. Thus, the previously-described compoundsand their salts show bacteriostatic and bactericidal activities againststreptococci, such as Streptococcus pyogenes, and staphylococci, such asStaphyloccus aureus, and may, therefore, be used as bacteriostatic andbactericidal agents to prevent and/or combat infections of such bacteriain animals or humans. Particularly good bacteriostatic and bactericidaleffects are shown by compounds of the formula represented by compoundsof the formula in which Alk" represents a lower alkylene radicalcontaining from eight to twelve carbon atoms and separating the two4-amino-1-piperidino groups by the same number of carbon atoms, andtheir addition salts with mineral jacids, e.g. hydrochloric, sulfuric orphosphoric acid, lower alkane carboxylic acids, e.g. acetic or propionicacid, lower alkane dicarboxylic acids, e.g. maleic acid, lowerhydroxye.g. tartaric acid, or lower hydroxy-alkane tricarboxylic acids,e.g. citric acid. This group of compounds may be represented by1,10-bis-(4- amino-l-piperidino)-decane of the formula and the salts,particularly salts with the above-mentioned monobasic and dibasic acids.

.The new compounds of this invention may be used as medicaments in theform of pharmaceutical preparations, which contain the newbis-(amino-l-piperidino)-alkane compounds or their salts, especiallytheir pharmacologically compatible acid addition salts, in admixturewith a pharmaceutical organic or inorganic, solid or liquid carriersuitable for enteral, parenteral or topical administration. For makingup the preparations there may be employed substances, which do not reactwith the new compounds, such as water, gelatine, lactose, starches,stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils,benzyl alcohols, gums, propylene glycol, polyalkylene glycols or anyother known carrier for medicaments. The pharmaceutical preparations maybe in solid form, for example, as capsules, tablets or dragees and thelike, in liquid form, for example, as solutions, e.g. isotonic salinesolutions, or as suspensions, emulsions or creams and the like. Ifdesired, they may contain auxiliary substances such as preserving,stabilizing, wetting or emulsifying agents, salts for varying theosmotic pressure or buflfers, and the like. They may also contain, incombination, other therapeutically useful substances.

Advantageously the compounds of the present invention may be prepared bytreating compounds of the formula in which Alk has the above-givenmeaning, each of the radicals Py and Py represents an amino-l-pyridiniumgroup (amino having the previously-given meaning), and

An stands for the anion of an acid, with a reducing reagent, and, ifdesired, converting a primary or a secondary amino group in a resultingcompound into a secondary or a tertiary amino, or, if desired, acylatinga resulting compound, containing primary or secondary amino groups,and/or, if desired, hydrolyze compounds containing N- acyl groups, and/or, if desired, converting a resulting salt into the free base, and/ or,if desired, converting a free base into its salts, and/or, if desired,converting in a resulting compound tertiary amino groups into quaternaryammonium groups, while temporarily protecting any primary or secondaryamino groups, and/ or, if desired, separating resulting mixtures ofracemates into single racemates, and/or, if desired, resolving resultingracemates into antipodes.

In the above formula, depicting the starting materials, An standsprimarily for the anion of a strong inorganic acid, such as a mineralacid, particularly a hydrohalic acid, especially hydrobromic acid, or ofa strong organic sulfonic acid, such as a monocyclic carbocyclic arylsulfonic acid, particularly p-toluene sulfonic acid. Anions of otherinorganic or organic acids may also be conceivable, whereby anions ofdi-basic acids, such as, for example, sulfuric or tartaric acid maysatisfy two positive pyridinium ions.

Reducing reagents capable of converting the bis-(amino-1-pyridinium)-alkane compounds into the desired bis-(amino-l-piperidino)-alkanes are primarily hydrides, especiallyborohydrides, such as alkali metal borohydride, e.g. lithiumborohydride, sodium borohydride or potassium borohydride, alkaline earthmetal borohydrides, e.g. calcium borohydride, strontium borohydride orbarium borohydride, or alkali metal tri-lower alkoxy-borohydrides, e.g.sodium trimethoxy-borohydride. Alkali metal tri-loweralkoxy-aluminumhydrides, e.g. lithium tri-propyloxy-aluminumhydride, mayalso be used as reducing agents. If desired, these reagents may be usedtogether with an activator, such as, for example, aluminum chloride andthe like. Solvents used in the reaction are, for example, loweralkanols, e.g. methanol or ethanol, or any other solvent compatible withthe above-mentioned metal hydride compounds. The reaction may be carriedout under cooling or at room temperature, and, if necessary, may becompleted at an elevated temperature. If desired, it may be performed inthe atmosphere of an inert gas, e.g. nitrogen.

Another reducing reagent capable of converting bis- (amino-l-pyridinium)-alkane compounds into the correspondingamino-l-piperidino derivatives, may be catalytically activated hydrogen,whereby the catalyst contains a metal of the eighth group of theperiodic system, such as platinum or palladium; preferred catalysts are,for example, platinum oxide and palladium on charcoal. Thishydrogenation may be carried out in the presence of a solvent, such as alower alkanoic acid, e.g. acetic acid, or a lower alkanol, e.g. methanolor ethanol, and the like; it may be performed under atmospheric orincreased pressure, and, if desired, at an elevated temperature.

Nascent hydrogen, such as generated by a metal or a metal amalgam in thepresence of a hydrogen donor, may also be used in the above-describedreduction procedure; zinc in the presence of acetic acid or aluminumamalgam in the presence of a moist ether, e.g. tetrahydrofuran, areexamples of sources of nascent hydrogen capable of performing thedesired reaction.

The resulting bis(amino l-piperidino)-alkanes may be isolated accordingto conventional methods; for example, an alcoholic solvent used in themetal hydride reduction may be evaporated, the residue suspended in asmall amount of water and salted out into a supernatant, only partiallywater-miscible solvent, e.g. ether, by adding, for example, a solidcarbonate, e.g. sodium or potassium carbonate, or an alkali metalhalide, e.g. sodium chloride. .The separated and dried organic, e.g.ether, phase may be evaporated and the liquid may be decanted from a,

residue after standing. The resulting free base may be purified bydistillation, for example, in a molecular still, or, moreadvantageously, by conversion into a salt or into another derivativethereof, which may be further purified, for example, byrecrystallization, if desired, in the presence of an adsorbent, e.g.charcoal, diatomaceous earth and the like.

The bis-amino-l-pyridinium-alkane compounds of the previously-givenformula, which are used as the starting materials, are known or, if new,may be prepared according to the procedures used for the knowncompounds. They may be prepared, for example, by reacting two mols of anamino-pyridine compound with one mole of a reactive ester formed by adihydroxy-alkane, in which the two hydroxyl groups are separated by atleast four carbon atoms, and a strong inorganic acid, such as a mineralacid, particularly a hydrohalic acid, e.g. hydrobromic acid, or a strongorganic sulfonic acid, such as a monocyclic carbocyclic aryl sulfonicacid, e.g. p-toluene sulfonic acid. The reaction may be carried out inthe presence of an inert solvent, such as, for example, a carbocyclicaryl hydrocarbon, e.g. benzene, toluene or xylene, a highboilingaliphatic hydrocarbon, e.g. hexane and the like, a lower alkanone, e.g.Z-butanone, or a lower alkanol, e.g. isopropanol. It is advantageouslyperformed at an elevated temperature, preferably at the boilingtemperature of the solvent.

Particularly useful as starting materials are compounds of the formulain which Alk represents an alkylene radical containing from six tofourteen carbon atoms and separating the two groups Py by four tofourteen carbon atoms, and in which Py represents a 4-amino-l-pyridiniumand Hal stands for the anion of a hydrohalic acid. This group ofstarting materials may be represented by compounds of the formula inwhich Alk" represents an alkylene radical containing from eight totwelve carbon atoms and separating the two 4-amino-1-pyridinium groupsby the same number of carbon atoms.

In the compounds resulting from the above-described procedure, primaryor secondary amino groups may be converted into secondary or tertiaryamino groups according to conventional methods. For example, compoundsvvith primary amino groups may be treated with an aldehyde to formso-called Schiif bases, which upon reduction (for example, with sodiumborohydride) yield compoundscontaining secondary amino groups. Suchgroups may also be obtained by reducing in N-acy-lated amino groups theamido into a methylene-amino group; the reduction may be carried out,for example, by treatment with an alkali metal aluminum hydride, e.g.lithium aluminum hydride, in an inert solvent, e.g. ether, whereby itmay be advantageous to use an activator, such as aluminum chloride. Thereduction of amides into amino groups is also suitable for thepreparation of tertiary amino groups; upon treatment of an N-acylatedsecondary amino group with aluminum hydride, the tertiary amino groupmay be formed.

Tertiary, as Well as secondary, amino groups may be formed from primaryamino groups, for example, by treatment of the amino compounds withcatalytically activated hydrogen in the presence of an aldehyde or aketone. A catalyst contains a metal of the eighth group of the periodicsystem, such as palladium (palladium on charcoal), platinum (platinumoxide or platinum black) or nickel (Raney nickel) and the like; hydrogenmay be applied under atmospheric, as well as under increased pressure.Any aldehyde or ketone compound suitable in the formation of thepreviously-shown secondary or tertiary amino groups may be used; forexample the use of formaldehyde in the above reaction furnishes methylgroups, whereas acetone yields isopropyl groups.

The formation of secondary and tertiary amino groups from primary orsecondary amino groups may also be achieved by treatment of the latterwith esters, formed by hydroxylated compounds and strong acids,particularly hydrohalic acids; this reaction may be carried outaccording to known procedures, such as, for example, according to theconditions used for the alkylation of primary and secondary amino groupswith lower alkyl halides, e.g. methyl, ethyl, n-propyl or isopropylchloride, bromide or iodide and the like.

Compounds, prepared according to the procedure of this invention, whichcontain primary or secondary amino groups, may be converted intoacylated derivatives according to procedures used for the preparation ofnitrogen-acylated derivatives. N-acylation may be carried out, forexample, by treating the amino compound with a reactive functionalderivative of one of the carboxylic acids mentioned hereinbefore, suchas a halide, e.g. chloride, or an anhydride. The reaction may be carriedout according to known procedures, for example, in the absence orpresence of a condensing reagent, such as a liquid organic base, forexample, a tri-lower alkyl-amine, e.g. trimethylamine or triethylamine,or preferably a pyridine derivative, e.g. pyridine or collidine,particularly if an anhydride, e.g. acetic acid anhydride is used.Solvents are anhydrous inert organic solvents, such as, for example,lower aliphatic ketones, e.g. acetone. Liquid basic condensationreagents, such as, for example, pyridine or collidine, maysimultaneously serve as solvents. A liquid acylation reagent, such as,for example, acetic acid anhydride, may be used without an additionalsolvent. Depending on the number of available primary or secondary aminogroups, the conditions of the reaction, and/or the molar ratios of thereactants, monoor poly-acylated products may be obtained.

N-acylated derivatives may be converted into nonacylated compounds, forexample, by acidic or basic hydrolysis. Particularly susceptible tohydrolytic cleavage are N-acylated amino compounds, in which the acylgroup is derived from an O-lower alkyl-carbonic acid, e.g. O-methyl-carbonic or O-ethyl carbonic acid, or a polyhalogene-lower alkanecarboxylic acid, e.g. trifluoroacetic acid. Certain N-acylated aminogroups may also be converted to non-acylated amino groups byhydrogenolysis; for example, compounds containing N-acyl-amino groups,in which acyl represents the acyl radical of an O-benzyl-carbonic, e.g.O-benzyl-carbonic acid, may be treated with hydrogen in the presence ofa catalyst, such as palladium on charcoal, to cleave the N-acylatedamino group.

Compounds of the present invention, which contain N- acyl-amino groups,particularly those which are easily cleaved by hydrolysis orhydrogenolysis, are, therefore, particularly suitable as intermediarycompounds. Thus, reactions on compounds containing N-acylated amino maybe carried out, which otherwise would affect free primary or secondaryamino groups; thetemporary protection of the latter by way of removableacyl groups makes such reactions possible. After completion of thelatter, compounds containing N-acylated groups may then be reconvertedinto compounds containing free primary or secondary amino groups.Acylation and deacylation may be carried out according to thepreviouslydescribed or analogous procedures.

The compounds of this invention may be obtained in the form of freebases or as thesalts thereof. A salt may be converted into the freebase, for example, by reacting the former with an alkaline, particularlyan aqueous alkaline, reagent, such as an alkali metal hydroxide, e.g.lithium, sodium or potassium hydroxide, an alkali metal carbonate, e.g.sodium or potassium carbonate or hydrogen carbonate, or ammonia. A freebase may be converted into its therapeutically useful acid additionsalts by reacting the free base with one of the inorganic or organicacids outlined hereinbefore; salt formation may be carried out, forexample, by treating a solution of the free base in a solvent, such as alower alkanol, e.g. methanol, ethanol, n-propanol or isopropanol and thelike, or other suitable solvents with the acids or a solution thereofand isolating the resulting salt, for example, by adding anothersolvent, such as an ether, e.g. diethylether, and thus precipitating thesalt, or by any other standard procedure. The salts (monoor poly-salts)may also be obtained as the hemihydrates, monohydrates, sesquihydratesor polyhydrates depending on the conditions used in the formation of thesalts.

Quaternary ammonium compounds may be formed from the compounds of thisinvention. Prior to quaternization, groups, such as primary or secondaryamino groups, may temporarily be protected, for example, by easilyremovable acyl groups, such as those shown hereinbefore. Thequaternization reaction may be carried out, for example, by treating thefree base with an ester formed by a hydroxylated compound and a stronginorganic or organic acid. Hydroxylatcd compounds are primarily loweralkanols containing from one to seven carbon atoms, and esters thereofare more especially those with mineral acids, such as hydrohalic acids,e.g. hydrochloric, hydrobromic or hydriodic acid, or with organicsulfonic acids, such as lower alkane sulfonic acids, e.g. methane,ethane or Z-hydroxy-ethane sulfonic acid and the like. Such esters are,for example, lower alkyl halides, e.g. methyl, ethyl, n-propyl orisopropyl chloride, bromide or iodide and the like, or lower alkyl loweralkane sulfonates, e.g. methyl or ethyl methane sulfonate, ethanesulfonate or Z-hydroxy-ethane sulfonate. The reaction may be performedadvantageously in the presence of a solvent, such as a lower alkanol,e.g. methanol, ethanol, propanol, isopropanol, butanol or pentanol, alower alkanone, e.g. acetone or methyl ethyl ketone, or an organic acidamide, e.g. formarnide or dimethylformamide, if necessary, at anelevated temperature, and/or in a closed vessel under pressure.

Quaternary ammonium compounds obtained may be converted into thecorresponding quaternary ammonium hydroxides, for example, by reacting aquarternary ammonium halide with silver oxide, or a quarternary ammoniumsulfate with barium hydroxide, by treating a quaternary ammonium saltwith an anion exchanger, or by electrodialysis. From a resultingquaternary ammonium hydroxide there may be prepared therapeuticallysuitable quaternary ammonium salts by reacting the former with an acid,for example, with one of those described hereinbefore as being suitablefor the preparation of the acid addition salts. A quaternary ammoniumcompound may also be converted directly into another quaternary ammoniumsalt without forming the quaternary ammonium hydroxide; for example, aquaternary ammonium iodide may be reacted with freshly prepared silverchloride to yield the quaternary ammonium chloride, or a quaternaryammonium iodide may be converted into the corresponding chloride bytreatment with hydrochloric acid in anhydrous methanol. Quaternaryammonium compounds may also crystallize as hydrates, e.g. hemihydrates,monohydrates, sesquihydrates or polyhydrates.

The new compounds of this invention may be obtained as mixtures ofracemates, which mixtures may be separated into the individual racemateson the basis of physico-chemical differences, such as solubility; suchseparation may be carried out, for example, by fractionatedcrystallization or distillation.

The racemates of the compounds of this invention may be resolved intothe optically active dand l-forms according to procedures known for theresolution of racemic compounds. For example, the free base of a racemicd,lcompound may be dissolved in a solvent, such as, for

example, a lower alkanol, e.g. methanol or ethanol, and one of theoptically active forms of an acid containing an asymmetric carbon atom,or a solution thereof, for example, in the same lower alkanol or inanother solvent may then be added, whereupon a salt can be isolated,which is formed by the optically active acid with one of the opticallyactive form of the base. Especially useful as optically active forms ofsalt-forming acids having an asymmetric carbon atom are D- andL-tartaric acid; the optically active forms of malic, mandelic, camphorsulfonic or quinic acid may also be employed. From resulting salts, thefree and optically active base may be obtained according to processesknown for the conversion of a salt into a base, for example, 'asoutlined hereinbefore. An optically active base may be converted intoacid addition salts with one of the acids mentioned hereinbefore, or maybe converted into other derivatives thereof. Optically active forms mayalso be isolated by biochemical methods.

The invention also comprises any modification of the process wherein acompound obtainable as an intermediate at any stage of the process isused as starting material and the remaining step(s) of the processis(are) carried out, as well as any new intermediates.

In the process of this invention such starting materials are preferablyused which lead to final products mentioned in the beginning aspreferred embodiments of the invention.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees centigrade.

Example 1 A solution of 31.1 g. of1,10-bis-(4-amino-1-pyridinium)-decane dibromide in about 500 ml. ofmethanol is treated with a large excess of sodium borohydride (a totalof about g.) in portions and over a period of several hours. At thebeginning, the reaction proceeds exothermically and causes someevaporation of the methanol, which is replenished. After the initialexothermic reaction subsides, the reaction mixture is heated on thesteam bath; additional sodium borohydride is added while heating. Thesolvent is then allowed to evaporate until a thick suspension is formed,which is cooled and treated with 150 ml. of water. Several hundred gramsof potassium carbonate is added, and the organic material is extractedwith three portions of ether (a total of about 2500 ml.). The ethersolution is dried over potassium carbonate, filtered and evaporated. Theresidue is allowed to stand for several days; the liquid portion,representing the 1,10- bis-(4-amino-l-piperidino)-decane, is decantedfrom the solid phase.

It is converted into the salt as follows: A solution of the base inethanol is treated with an excess of dry hydrogen chloride, theprecipitate is filtered ofi, washed with ethanol (yield: about 5 g.) andrecrystallized from the same solvent yielding thel,10-bis-(4-amino-l-piperidino)- decane tetrahydrochloride, M.P. 285.The hydrogen chloride may be replaced by other acids, such as, forexample, sulfuric, phosphoric, maleic, tartaric or citric acid and thelike may be used as salt-forming acids, whereupon the correspondingsulfate, phosphate, maleate, tartrate or citrate and the like ofl,lO-bis-(4-amino-l-piperidino)-decane may be isolated.

The starting material may be prepared as follows: A mixture of 15.5 g.of Z-aminopyridine, 25 g. of l,l0-dibromodecane and 250 ml. of tolueneis refluxed for five hours. A crystalline, tan precipitate is formed,the reaction mixture is cooled and the solid material is collected,dried and recrystallized from ethanol to give the colorlessl,lO-bis-(4-amino-l-pyridinium)-decane dibromiide, M.P. 247; yield ofcrude material; 41.4 g.

Example 2 The 1,4-bis-(4-amino-1-piperidino)-butane tetrahydrochloride,M.P. 305, may be prepared by reacting 1,4-dibromobutane with4-amino-pyridine, reducing a methanol solution of the resulting1,4-bis-(4-amino-l-pyridinium)- butane di bromide, M.P. 275, with sodiumborohydride and converting the resulting free base into the saltaccording to the procedure described in Example 1.

Example 3 Treatment of 1,6-bis(4-amino-l-pyridinium) -hexane dibromide,M.P. 305, which may be prepared by reacting l,6-dibnomohexane with4-amino-pyridine, with sodium borohydride in the presence of ethanolgives rise to the formation of 1,6-bis-(4-amin-o-l-piperidino)-hexane,identified as the tetrahydrochloride melting at 204.

Example 4 A solution of 1,8-dibromooctane and 4-amino-pyridine, whenrefluxed according to the procedure of Example 1, yields the1,8bis-(4-amino-l-pyridinium)-octane dibromide, M.P. 302, which isreduced to the desired 1,8bis- (4-amino-1-piperidino)octane by treatmentof a methan- 01 solution of the former with sodium borohydrid accordingto the process described in Example 1; the free base is converted to thetetnahydrochloride, M.P. 306, by treatment with hydrogen chloride.

Example 5 The reduction of 1,9-bis-(4-amino-l-pyridinium)-non- 'anedibromid'e, M.P. 222 (prepared from 1,9-dibromononane and4-amino-pyridine), with sodium borohydride in the presence of methanolyields the 1,9-bis-(4-aminopiperidino)-nonane, characterized as thetetrahydrochloride, M.P. 321. The reactions are carried out according tothe procedure of Example 1.

Example 6 The 1,12-bis-(4-amino-1-piperidino)-dodecane may be preparedby treating a methanol solution of 1,12-bis-(4-amino-Lpyridinium)-dodecane dibromide, M.P. 210, with sodium borohydrideaccording to the pnocedure described in Example 1; the free base may becharacterized as its tetra-hydrochloride.

The starting material may be prepared as previously shown, i.e. byrefluxing a toluene solution of 1,12-dibromododecane With4-amino-pyridine.

Example 7 1,8-dibromo-octane and 4amino-2methyl-pyridine, when refluxedin a toluene solution, yields the 1,8-bis-(4- amino 2 methylpyridinium)-octane dibromide, M.P. 308, which is reduced by treatment ofmethanol solution thereof with sodium borohydride, to yield the desired1,8-bis- 4-amino-2-methyll-piperidino -o ctane, characterized as thetetrahydrochloride.

Example 8 The reaction of a methanol solution of 1,10-bis-(3-amino-1-pyridinium)-decane dibromide, which is prepared by reacting3-amino-pyridine with 1,10-dibromodecane in toluene, with hydrogen inthe presence or platinum yields the desired 1, 1 O-bis- 3-amino- 1apiperidino -decane, identified as its tetrahydrochloride.

Example 9 10 thereof with sodium borohydride according to the procedureof Example 1 yields the 1,10-bis-(4-amino-1- piperidinO)-undecane; thetree base may be converted and characterized as the tetrahydrochloride.

Example 1] Treatment of an ethanol solution of 1,10-bis-(4 amino-1-piperidino)-deoane with hydrogen in the presence of palladium oncharcoal and an excess of an aqueous solution of formaldehyde results inthe formation of the 1,10- bis-(4-dimethylamino-1-piperidino) -decane.

Example 12 Upon reacting the 1,10-bis-(4-amino-1-piperidino)- decanewith trifluoroacetic acid anhydride in the presence of pyridine the1,10-bis-[4-(N-trifluoroacetylamino)-l piperidino1-decane may beobtained, which, when treated with methyl iodide, yield-s the1,10-bis-[4-(N-trifluoroacetylarnino)-1-piperidinium]-decane di-iodide.The N- trifluoroacetylamino groups of the resulting compound may behydrolyzed by treatment With sodium hydroxide to yield the desired1,10-bis-(4-amino-1-piperidinium)- decane di-iodide.

The compounds of the present invention may also be prepared according toother procedures. For example, in bis-l-piperidino-alkane compounds, inWhich the piperidino groups contain functional substituents capable ofbeing converted into amino groups of the previously- :mentioned type,such groups may be converted into amino groups, and, if desired, theoptional steps may be carried out.

Functional groups Which may be converted into amino groups are primarilycarboxyl groups, or particularly functional derivatives thereof.Functional derivatives of carboxyl groups are primarily their estersWith lower alkanols, e.g. methanol or ethanol, which are capable ofbeing converted via hydrazides into azides; under the congroup may alsobe obtained directly from the carboxyl group by treatment with hydrazoicacid; this reaction may be carried out in the presence of sulfuric acidand directly furnish the desired amino group. This latter modificationis carried out according to the conditions of the Schmidt reaction.

Carbamyl represents another functional derivative of a carboxylic acid,which may be converted to an amino group, for example, according to theHofmann degradation reaction. This reaction involves bromination of thecarbamyl group and rearrangement of the brominated cgrbomyl group in thepresence of an alkali metal hydroxi e. T

' 11 dino)-alkanes may then contain secondary or tertiary amino groupsin the piperidyl moiety.

Previously-described bis-(1-piperidino)-alkane compounds, which containN-acylamino groups in the piperidino moieties, may also be used for thepreparation of the desired bis-(amino-l-piperidino)-alkane derivatives;the hydrolysis may be carried out as previously described. Thesebis-(N-acylamino-l-piperindo)-alkanes may be obtained by treating areactive ester of a bis-hydroxy-alkane, in which the hydroxyl groups areseparated by at least four carbon atoms, for example, abis-dihalogeno-alkane, e.g. a bis-bromo-alkane, with an(N-acylamino)-piperidine. The resulting compounds may then be hydrolyzedto the amino derivatives according to previously-described procedures.

The compounds of the presentainvention may also be obtained by reactinga bis-amino-alkane, in which the amino groups are separated by at leastfour carbon atoms, with a reactive ester of a 1,5-dihydroXy-pentane,such as a 1,5-dihalogeno-pentane, e.g. a 1,-5-dibromo-pentane, whichcontains, in addition to the ester groupings, an amino group; thisreaction, in which piperidino-nuclei are formed, may be carried outaccording to known conditions.

Compounds of this invention, which have the previously-given formula inwhich Alk has the above-mentioned meaning, and the two radicals Pi andPi are amino-l-piperidyl radicals, but of difierent structure, may beobtained, whenever the starting materials are prepared stepwise.

What is claimed is:

1. A member of the group consisting of compounds of the formula:

Pi-AlkPi' O-phenyl-lower alkyl-carbonic acid, lower alkane car- 4boxylic acid, trifluoroacetic acid, benzoic acid and phenylloweralkanoic acid, therapeutically acceptable acid addition salts thereof,quaternary ammonium hydroxides thereof, lower alkyl quaternary ammoniumhalides there- 12 of and lower alkyl quaternary ammonium sulfonatesthereof.

2. Compounds of the formula:

in which Alk represents an alkylene radical containing from six tofourteen carbon atoms and separating the two groups Pi, by four tofourteen carbon atoms, and Pi, represents 4-amino-l-piperidino.

3. Compounds of the formula:

in which Alk represents an alkylene radical containing from eight totwelve carbon atoms and separating the two 4-amino-1-piperidino groupsby the same number of carbon atoms.

4. 1,8-bis-(4-amino-1-piperidino)-octane.

5. l,9-bis-(4amino11-piperidin0)-n0nane.

6. 1,10-bis-(4-amino-1-piperidino)-decane.

7. 1,10-bis-(4-amino-l-piperidino)-decane tetrahydrochloride.

8. 1,-10-bis-(4-amino-1-piperidino)-undecane.

9. 1,12-bis-(4-amino-1-piperidino)-dodecane.

10. Process for the preparation of a compound of the formula:

Pi-Alk-Pi in which Alk represents an alkylene radical separating groupPi from group Pi by four to twenty carbon atoms, and each of the groupsPi and Pi stands for a member selected from the group consisting of3-amino-1-piperidino and 4-amino-1-piperidino, which comprisescontacting a compound, in an inert solvent, of the formula:

[PyAlkPy1 21 in which Alk has the above-given meaning, each of Py and Pyrepresents a member selected from the group consisting of3-amino-l-pyridino and 4-amin0-1-pyridino, and An stands for the anionof an acid, with an alkali metal borohydride reducing agent.

References Cited in the file of this patent UNITED STATES PATENTS2,261,002 Ritter Oct. 28, 1941 2,271,378 SeaIle Jan. 27, 1942 2,716,134Reynolds et a1 Aug. 23, 1955 FOREIGN PATENTS 536,017 Great Britain Apr.30, 1941

1. A MEMBER OF THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA: